negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell. [GOC:obol]

Negative regulation of T cell activation via T cell receptor (TCR) contact with antigen bound to MHC molecule on antigen presenting cell (APC) is a critical process that prevents excessive immune responses and maintains immune homeostasis. It involves a complex interplay of signaling pathways and regulatory molecules, ensuring that T cells are only activated when necessary and avoiding autoimmune reactions.

Here's a detailed breakdown of the process:

1. **Antigen Presentation:** APCs, such as dendritic cells, macrophages, and B cells, engulf antigens and process them into small peptides. These peptides are then displayed on the cell surface bound to MHC molecules (MHC I for CD8+ T cells and MHC II for CD4+ T cells).
2. **TCR Recognition:** The TCR on the surface of T cells recognizes and binds to the specific antigen-MHC complex. This interaction triggers the activation of the TCR signaling cascade.
3. **Signal Transduction:** TCR engagement initiates a series of signaling events involving various intracellular molecules, including tyrosine kinases (Lck, Fyn), the ζ chain of the TCR complex, and downstream signaling molecules like ZAP70 and PLCγ1.
4. **Calcium Signaling:** Activation of PLCγ1 leads to the hydrolysis of phosphatidylinositol bisphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3). IP3 triggers the release of calcium ions (Ca2+) from intracellular stores, leading to increased intracellular calcium levels.
5. **Activation of Transcription Factors:** The rise in intracellular calcium activates calcineurin, a phosphatase that dephosphorylates the transcription factor NFAT (nuclear factor of activated T cells). De-phosphorylated NFAT translocates to the nucleus, where it interacts with other transcription factors, such as AP-1 and NF-κB, to initiate gene expression.
6. **Negative Regulatory Mechanisms:**
* **CTLA-4 and PD-1:** These inhibitory receptors are expressed on activated T cells. They bind to their ligands (CD80/CD86 for CTLA-4 and PD-L1/PD-L2 for PD-1) on APCs. This interaction triggers inhibitory signaling pathways, leading to downregulation of TCR signaling and suppression of T cell activation.
* **Phosphatases:** Several phosphatases, including SHP-1 and SHP-2, dephosphorylate key signaling molecules involved in TCR activation, thus terminating the signaling cascade.
* **Apoptosis:** In the absence of sufficient costimulatory signals, activated T cells can undergo apoptosis (programmed cell death), preventing excessive immune responses.
* **Treg Cells:** Regulatory T cells (Tregs) play a crucial role in suppressing T cell activation. They express high levels of CTLA-4 and other inhibitory molecules and secrete immunosuppressive cytokines like IL-10 and TGF-β.

The intricate balance between positive and negative regulatory mechanisms ensures that T cell activation is tightly controlled, preventing autoimmune reactions and maintaining immune tolerance. These negative regulatory mechanisms are essential for preventing excessive immune responses and maintaining immune homeostasis.'
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Compounds (10)